Minimal Residual Disease, Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of donor lymphocyte infusions when given together with daratumumab and to see how well they work in treating participants with acute myeloid leukemia that has come back after a stem cell transplant. A donor lymphocyte infusion is a type of therapy in which lymphocytes (white blood cells) from the blood of a donor are given to a participant who has already received a stem cell transplant from the same donor. The donor lymphocytes may kill remaining cancer cells. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Giving daratumumab and donor white blood cells may work better in treating participants with acute myeloid leukemia.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate safety and tolerability of daratumumab and escalating doses of donor lymphocyte infusions (DLI) in post-hematopoietic cell transplantation (HCT) patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transformed to AML (phase I). II. To evaluate overall response rate to daratumumab and DLI in patients with post-HCT relapsed AML and MDS (phase II). SECONDARY OBJECTIVES: I. To assess overall response rates in minimal residual disease (MRD) positive patients and in patients with overt morphological relapse. II. To assess MRD conversion rates from MRD positive to MRD negative. III. To determine the post-relapse 6-month overall response (OS) rates of patients with relapsed AML and MDS following allogeneic hematopoietic stem cell transplantation (allo-HSCT) who are treated with daratumumab. IV. To determine the rates of graft-versus-host disease (GVHD) (both grades II-IV and III-IV) and autoimmune side effects of daratumumab. V. To determine the post-relapse 6-month progression-free survival (PFS) rates of patients with relapsed AML and MDS following allo-HSCT who are treated with daratumumab. EXPLORATORY OBJECTIVES: I. To compare CD38 expression levels in myeloid blasts and interferon gamma (IFN-y) levels in plasma at the time of relapse before starting daratumumab and at progression or relapse after daratumumab. II. To compare peripheral blood T cell number and subsets (CD3, CD4, CD8, (CD38 expression on regulatory T cells \[T-regs\], CD4 and CD8), T regs, B-regulatory cells, natural killer (NK) cell numbers and bone marrow T cell subsets at the time of relapse before starting daratumumab, at the time of partial/complete response to daratumumab, and at the time of progression or relapse after daratumumab. III. To evaluate whether daratumumab has (i) direct anti-leukemia effects (ii) antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and (III) immune modulation of autologous immune system (NK cells, T cells, T-regs, B-regulatory cells \[B-regs\], and myeloid-derived suppressor cells \[MDSCS\]) in AML. IV. To evaluate the effect of daratumumab on exosome content and clearance along with other soluble factors in AML. V. To evaluate serum interferon (IFN) levels pre-daratumumab, during and post-daratumumab. VI. To evaluate whether fratricide occurs in patients treated with daratumumab. OUTLINE: This is a phase I, dose escalation study of donor lymphocyte infusions followed by a phase II study. Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity. Participants found to be in complete response (CR) at the end of 8 weeks may receive daratumumab IV once every 2 weeks for 8 weeks, and then once monthly for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up for 1 year.
Interventions
BIOLOGICALDaratumumab
Given IV
PROCEDUREDonor Lymphocyte Infusion
Given via infusion
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
Sumithira Vasu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* AML relapse following Allo-HSCT (Morphological relapse, or MRD positive verified by flow cytometry, cytogenetics, and molecular mutations) * Relapsed/Refractory AML must not be candidates for available therapies known to be effective for treatment of their AML. * MDS transformed to AML following Allo-HCT * Patients who received a 10/10 HLA-matched allogeneic HCT either from sibling donors or unrelated donors or atleast a 5/10 haploidentical transplant. * Engraftment must have occurred as defined by platelet (PLT) count \> 20,000/µL and ANC * 0.5 * Eastern Cooperative Oncology Group (ECOG) performance status \< 3 * Creatinine clearance \> 40 ml/min (calculated or measured) * Aspartate aminotransferase (AST) \< 3 x upper limit of normal (ULN), alanine aminotransferase (ALT) \< 3 x ULN * Total bilirubin \< 1.5 x ULN * Off calcineurin inhibitors for at least 2 weeks * Prednisone dose ≤ 20 mg/day * Patients with proliferative disease can be cytoreduced with cytotoxic chemotherapy at Investigator discretion, but there should be at least a 14 day window between start of cytoreductive therapy and start of daratumumab * Blast count ˂20K/day (hydrea use is allowed)
Exclusion criteria
* No demonstrable evidence of donor chimerism (˂ 55% donor CD3 or CD33 chimerism) * Patients with a molecular mutation without chromosomal abnormalities or declining chimerisms (MRD status must be verified by surface marker and mutational analyses) * Active graft-versus-host disease (GvHD) grades II-IV; prior acute GVHD could have occurred but resolved at time of initiation of daratumumab * Extensive chronic GvHD requiring ongoing immunosuppression with calcineurin inhibitors * Patients with FLT3+ AML or blast crisis CML who have not yet received post-transplant TKI therapy * Active central nervous system (CNS) disease testicular disease EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.; seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy). * Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification. * History of grade IV anaphylactic reaction to monoclonal antibody therapy * Active autoimmune disease prior to transplant * Concurrent use of any other investigational drugs
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and Feasibility Defined as the Establishment of the Appropriate Dose Level of Donor Lymphocyte Infusion When Given With a Fixed Dose of Daratumumab | Up to 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) Conversion Rates | Up to 6 months | — |
| Rates of Complete Remission | Up to 6 months | Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses. |
| Post-relapse Progression-free Survival | At 6 months | Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses. |
| Post-relapse Overall Survival | Up to 6 months | Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses. |
Other
| Measure | Time frame | Description |
|---|---|---|
| T-cell, NK Cell, B-cell, and Myeloid-derived Suppressor Cells (MDSC) Infiltration in Bone Marrow | Baseline to 6 months | This will be evaluated on bone marrow samples pre-and post-treatment with daratumumab. |
| Exosomes From Bone Marrow | Up to 6 months | This will be examined for both number and also content (protein, messenger ribonucleic acid \[mRNA\], and micro RNAs \[mIRs\]). |
| Serial Assessment of Microenvironment | Up to 6 months | Will be assessed with with stromal cell cultures. |
| Chimerism Analysis | Up to 6 months | Using single-nucleotide polymorphisms, relative contributions from donor vs. recipient in sorted CD3+ and CD33+ cells will be measured and expressed as a percentage. |
| Immune Reconstitution | Up to 6 months | Dr.Gerard Lozanski has developed a panel called the Immunome to study reconstitution of T cells, NK cells and B cells post-transplant. Specific information regarding stages of activation of T cells is also available from this panel. |
| Immune Response Post Daratumumab | Up to 6 months | — |
| Phenotypic Studies to Evaluate T Cell Exhaustion | Baseline to 6 months | This will be performed on bone marrow samples pre-and post-treatment with daratumumab. |
| Phenotypic Studies to Evaluate Activation Status of NK Cells | Baseline to 6 months | This will be performed on bone marrow samples pre-and post-treatment with daratumumab. |
| Measurements of Cytokines Including But Not Limited to Interferon Gamma (IFN-y) | Up to 6 months | This will be measured at relapse, pre and post daratumumab treatment. Exosomes from bone marrow will be examined at these serial times for both number and also content (protein, messenger ribonucleic acid \[mRNA\], and micro RNA \[mIRs\]). |
| Expression of CD38 on Bone Marrow | Up to 6 months | CD38 expression on bone marrow is checked prior to transplant. Most patients are in remission prior to transplant. Patients who were initially treated at Ohio State University (OSU) will have banked leukemia samples at the time of diagnosis. Expression of CD38 on samples at diagnosis and prior to transplant by immunohistochemical staining will be performed. |
| Expression of CD38 in Lymphocytes in Bone Marrow | Baseline to 6 months | Percentage of lymphocytes in bone marrow pre- and post-treatment with daratumumab will be studied. In addition to percentage, expression of CD38 on lymphocytes will be evaluated by immunohistochemistry (IHC). |
| Phenotypic Studies to Evaluate T Cell Exhaustion/Function | Baseline to 6 months | This will be performed on bone marrow samples pre-and post-treatment with Daratumumab at the specified time points. |
| Phenotypic Studies to Evaluate Activation Status of Natural Killer (NK) Cells | Up to 6 months | This will be performed on bone marrow samples pre-and post-treatment with daratumumab. |
Countries
United States
Participant flow
Pre-assignment details
Due to low enrollment dose levels were not increased during the study
Participants by arm
| Arm | Count |
|---|---|
| Cohort I (High Risk AML) Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity.
Daratumumab: Given IV
Donor Lymphocyte Infusion: Given via infusion
Laboratory Biomarker Analysis: Correlative studies | 2 |
| Cohort 2 (AML/MDS-relapsed After Allo-HSCT) Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity.
Daratumumab: Given IV
Donor Lymphocyte Infusion: Given via infusion
Laboratory Biomarker Analysis: Correlative studies | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Disease Progression | 2 | 1 |
Baseline characteristics
| Characteristic | Cohort I (High Risk AML) | Total | Cohort 2 (AML/MDS-relapsed After Allo-HSCT) |
|---|---|---|---|
| Age, Continuous | 70 years | 66.25 years | 62.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 2 patients | 4 patients | 2 patients |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 1 / 2 |
| other Total, other adverse events | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Safety and Feasibility Defined as the Establishment of the Appropriate Dose Level of Donor Lymphocyte Infusion When Given With a Fixed Dose of Daratumumab
Time frame: Up to 6 months
Population: Data was not collected due to participants not reaching time point
Secondary
Minimal Residual Disease (MRD) Conversion Rates
Time frame: Up to 6 months
Population: Data was not collected due to participants not reaching time point
Secondary
Post-relapse Overall Survival
Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses.
Time frame: Up to 6 months
Population: Data was not collected due to participants not reaching time point
Secondary
Post-relapse Progression-free Survival
Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses.
Time frame: At 6 months
Population: Data was not collected due to participants not reaching time point
Secondary
Rates of Complete Remission
Kaplan-Meier estimates of survival and relapse will be made. Response will be measured using standard criteria. For pre/post-treatment comparisons in the correlative part of the study, a paired t-test will be applied. Two-tailed p values \<0.05 will be considered statistically significant in all analyses.
Time frame: Up to 6 months
Population: Data was not collected due to participants not reaching time point
Other Pre-specified
Chimerism Analysis
Using single-nucleotide polymorphisms, relative contributions from donor vs. recipient in sorted CD3+ and CD33+ cells will be measured and expressed as a percentage.
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Exosomes From Bone Marrow
This will be examined for both number and also content (protein, messenger ribonucleic acid \[mRNA\], and micro RNAs \[mIRs\]).
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Expression of CD38 in Lymphocytes in Bone Marrow
Percentage of lymphocytes in bone marrow pre- and post-treatment with daratumumab will be studied. In addition to percentage, expression of CD38 on lymphocytes will be evaluated by immunohistochemistry (IHC).
Time frame: Baseline to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Expression of CD38 on Bone Marrow
CD38 expression on bone marrow is checked prior to transplant. Most patients are in remission prior to transplant. Patients who were initially treated at Ohio State University (OSU) will have banked leukemia samples at the time of diagnosis. Expression of CD38 on samples at diagnosis and prior to transplant by immunohistochemical staining will be performed.
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Immune Reconstitution
Dr.Gerard Lozanski has developed a panel called the Immunome to study reconstitution of T cells, NK cells and B cells post-transplant. Specific information regarding stages of activation of T cells is also available from this panel.
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Immune Response Post Daratumumab
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Measurements of Cytokines Including But Not Limited to Interferon Gamma (IFN-y)
This will be measured at relapse, pre and post daratumumab treatment. Exosomes from bone marrow will be examined at these serial times for both number and also content (protein, messenger ribonucleic acid \[mRNA\], and micro RNA \[mIRs\]).
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Phenotypic Studies to Evaluate Activation Status of Natural Killer (NK) Cells
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Phenotypic Studies to Evaluate Activation Status of NK Cells
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time frame: Baseline to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Phenotypic Studies to Evaluate T Cell Exhaustion
This will be performed on bone marrow samples pre-and post-treatment with daratumumab.
Time frame: Baseline to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Phenotypic Studies to Evaluate T Cell Exhaustion/Function
This will be performed on bone marrow samples pre-and post-treatment with Daratumumab at the specified time points.
Time frame: Baseline to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
Serial Assessment of Microenvironment
Will be assessed with with stromal cell cultures.
Time frame: Up to 6 months
Population: Not sufficient number of patients accrued to report on outcomes
Other Pre-specified
T-cell, NK Cell, B-cell, and Myeloid-derived Suppressor Cells (MDSC) Infiltration in Bone Marrow
This will be evaluated on bone marrow samples pre-and post-treatment with daratumumab.
Time frame: Baseline to 6 months
Population: Not sufficient number of patients accrued to report on outcomes